Analgesic and anti-inflammatory compositions containing cox-2 inhibitors

ABSTRACT

The present invention is directed to an analgesic composition which consists essentially of a cyclooxygenase-2 inhibitor and a compound selected from the group consisting of non-steroidal anti-inflammatory drugs, acetaminophen and mixtures thereof. The present invention further is directed to a method for inducing analgesia through the administration of such a composition to a patient.

FIELD OF THE INVENTION

[0001] This invention relates to a composition for alleviating painand/or inflammation which provides both quick onset and long duration.More particularly, this invention is concerned with a compositionconsisting essentially of a cyclooxygenase-2 inhibitor (also referred toas a cyclooxygenase II, COX-2 or COX II inhibitor) and a secondanalgesic composition selected from the group consisting of NSAIDS(non-steroidal, anti-inflammatory drugs), acetaminophen and mixturesthereof. The invention is also directed to a method for alleviating painand/or inflammation through the administration of such composition.

BACKGROUND OF THE INVENTION

[0002] Compounds have been found which exhibit anti-inflammatory,analgesic and antipyretic activity, (in addition to inhibitinghormone-induced uterine contractions and certain types of cancer growth)through inhibition of prostaglandin G/H synthase, also known ascyclooxygenase. Initially, only one form of cyclooxygenase was known,this corresponding to cyclooxygenase-1 or the constitutive enzyme, asoriginally identified in bovine seminal vesicles. This enzyme has beencloned, sequenced and characterized from various sources includingsheep, mouse and man. Prostaglandins have also been found to have bothphysiological and pathological roles. Cyclooxygenase-1 is responsiblefor endogenous basal release of prostaglandins and is important in theirphysiological functions such as the maintenance of gastrointestinalintegrity and renal blood flow. Non-steroidal anti-inflammatory drugs(NSAIDS) have been found to inhibit the cyclooxygenase-1 enzyme andthereby exhibit anti-inflammatory, analgesic and antipyretic properties.

[0003] While NSAIDS exhibit excellent anti-inflammatory, analgesic andantipyretic properties and possess additional benefits such as quickonset times, NSAIDS have a potential for gastrointestinal toxicity,and/or renal side effects.

[0004] More recently, the gene for a second inducible form ofcyclooxygenase, referred to as cyclooxygenase-2, has been cloned,sequenced and characterized in chicken, marine and human sources. Thisgene, termed cyclooxygenase-2, is rapidly and readily inducible by anumber of agents including mitogens, endotoxin, hormones, cytokines andgrowth factors. In contrast to cyclooxygenase-1, cyclooxygenase-2 ismainly responsible for the pathological effects of prostaglandins whererapid induction of the enzyme would normally occur in response to suchagents as inflammatory agents, hormones, growth factors, and cytokines.Therefore, a selective inhibitor of cyclooxygenase-2 has similaranti-inflammatory, analgesic and antipyretic properties to thoseobtained by inhibition of the cyclooxygenase-1 through use of an NSAIDS.

[0005] A number of cyclooxygenase-2 inhibitors are known. For example,cyclooxygenase-2 inhibitors are disclosed in U.S. Pat. Nos. 5,393,790;5,409,944; 5,418,254; 5,420,343; 5,436,265; 5,474,995; 5,476,944;5,486,534; 5,510,368; 5,521,213; 5,536,752; 5,547,975; 5,550,142;5,552,422; 5,565,482; 5,576,339; 5,580,985; 5,585,504; 5,593,994 and5,596,008.

[0006] While cyclooxygenase-2 inhibitors possess similaranti-inflammatory, analgesic and antipyretic activity to NSAIDS,cyclooxygenase-2 inhibitors also exhibit a diminished tendency to inducesome of the mechanism-based side effects that may occur with the use ofNSAIDs. In particular, cyclooxygenase-2 inhibitors appear to have areduced potential for gastrointestinal toxicity and renal side effects,a reduced effect on bleeding times and possibly a diminished ability toinduce asthma attacks in aspirin-sensitive asthmatic subjects.

[0007] However, while cyclooxygenase-2 inhibitors do possess potentialbenefits relating to reduced side effects, they are generally slowacting relative to cyclooxygenase-1 inhibitors such as NSAIDs oracetaminophen. Therefore, a patient using them for analgesia perceivesthat they possess an unsatisfactorily long onset period in providing thedesired analgesia.

[0008] The compositions claimed herein offer the benefits of quickeronset for analgesia relative to cyclooxygenase-2 inhibitors used alone.The claimed compositions further reduce the amount of cyclooxygenase-1inhibitors administered and thereby reduce the potential forgastrointestinal toxicity. Such combinations further provide longerduration of action, such as “once daily dosing”, without losing thebenefit of the fast onset of analgesia associated with the use ofcyclooxygenase-1 inhibitors. In still a further benefit of the presentinvention, the combinations of the claimed compositions are found to besynergistic in that the onset time of the cyclooxygenase-1 inhibitors(and therefore the claimed composition) is reduced relative to the onsettimes of either component used alone. In other words, the onset of thecyclooxygenase-1 inhibitor component (e.g. NSAID) is unexpectedlypotentiated by the presence of the cyclooxygenase-2 inhibitor.

SUMMARY OF THE INVENTION

[0009] In accordance with the present invention, a composition foralleviating pain and/or inflammation is provided which consistsessentially of (a) at least one cyclooxygenase-2 inhibitor and (b) atleast one compound selected from the group consisting of NSAIDs,acetaminophen and mixtures thereof.

[0010] Further in accordance with this invention, a method ofalleviating pain and/or inflammation is provided which comprisesadministering to a mammal exhibiting pain a composition consistingessentially of (a) at least one cyclooxygenase-2 inhibitor and (b) atleast one compound selected from the group consisting of NSAIDs,acetaminophen and mixtures thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The method of the claimed invention and the therapeuticcomposition therefore are applicable to the treatment of all varietiesof pain. The term “pain-alleviating” shall be understood herein toinclude the expressions “pain-suppressing” and “pain-inhibiting” as theinvention is applicable to the alleviation of existing pain as well asthe suppression or inhibition of pain which would otherwise ensue froman imminent pain-causing event. Any of the cyclooxygenase-2 inhibitorsheretofore used to alleviate pain can be used herein.

[0012] The expression “analgesia-inducing amount” as applied to thecyclooxygenase-1 inhibitors and/or cyclooxygenase-2 inhibitors employedin the therapeutic method and composition of this invention shall beunderstood to mean an amount thereof which when administered providessignificant analgesic activity.

[0013] Specific cyclooxygenase-2 inhibitors that can be used in thepractice of this invention are those compounds having a duration ofactivity of at least 12 hours. These include celecoxib, rofecoxib,meloxicam and nimesulide. Especially preferred are celecoxib androfecoxib.

[0014] Celecoxib is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideand is currently manufactured by G. D. Searle & Co. It is marketed underthe tradename Celebrex®. Rofecoxib is4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone and is currentlymanufactured by Merck & Co., Inc. It is marketed under the tradenameVioxx®. Meloxicam is4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2-H-1,2-benzothiazine-3-carboxamide1,1-dioxide. Its manufacture is disclosed in U.S. Pat. No. 4,233,299,the contents of which are hereby incorporated by reference. It isapproved for marketing in the United States under the tradename Mobic®.Nimesulide is N-(44-nitro-2-phenoxyphenyl)methanesulfonamide. Itsmanufacture is disclosed in U.S. Pat. No. 3,840,597, the contents ofwhich are hereby incorporated by reference.

[0015] With regard to the cyclooxgenase-1 inhibitor component, any ofthe NSAIDS, acetaminophen, or mixtures thereof used to alleviate painmay be used. The NSAIDS for use in the compositions and methods of thepresent invention can be selected from the following categories:

[0016] (1) the propionic acid derivatives;

[0017] (2) the acetic acid derivatives;

[0018] (3) the fenamic acid derivatives;

[0019] (4) the biphenylcarboxylic acid derivatives; and

[0020] (5) the oxicams.

[0021] The propionic acid derivatives for use herein include, but arenot limited to, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen,ketoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen andbucloxic acid. The propionic acid derivatives as herein defined arederivatives having a free —CH(CH₃)COOH or —CH₂CH₂COOH group (whichoptionally can be in the form of a pharmaceutically acceptable saltgroup, e.g. —CH(CH₃)COO⁻Na⁺ or —CH₂CH₂COO⁻Na⁺), typically attacheddirectly or via a carbonyl function to a ring system, preferably to anaromatic ring system. Structurally related propionic acid derivativeshaving similar analgesic and anti-inflammatory properties are alsointended to be encompassed by this group. Presently preferred members ofthe propionic acid group include ibuprofen, naproxen, flurbiprofen,fenoprofen, ketoprofen and fenbufen. Included within the description ofpropionic acid derivatives are isolated isomeric forms such as S+ibuprofen as disclosed in U.S. Pat. No. 4,851,444, the contents of whichare hereby incorporated by reference. Also within the practice of thepresent invention are the pharmaceutically acceptable salts thereof,e.g. naproxen sodium.

[0022] The acetic acid derivatives for use herein include, but are notlimited to, indomethacin, tolmetin, diclofenac, fenclofenac, alclofenac,ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetmitacin,fentiazac, clidanac and oxpinac. The acetic acid derivatives as hereindefined are derivatives having a free —CH₂COOH group (which optionallycan be in the form of a pharmaceutically acceptable salt group, e.g.—CH₂COO⁻Na⁺), typically attached directly to a ring system, preferablyto an aromatic or heteoaromatic ring system. Structurally related aceticacid derivatives having similar analgesic and anti-inflammatoryproperties are also intended to be encompassed by this group.

[0023] The fenamic acid derivatives for use herein include, but are notlimited to, mefenamic acid, meclofenamic acid, flufenamic acid, niflumicacid and tolfenamic acid. Structurally related fenamic acid derivativeshaving similar analgesic and anti-inflammatory properties are alsointended to be encompassed by this group. The fenamic acid derivativesas defined herein may contain a pendant —COOH group or apharmaceutically acceptable salt thereof e.g. in the form of a —COO⁻N⁺group.

[0024] The biphenylcarboxylic acid derivatives for use herein include,but are not limited to, flufenisal and diflunisal. Structurally relatedbiphenylcarboxylic acid derivatives having similar analgesic and/oranti-inflammatory properties are also intended to be encompassed by thisgroup. The fenamic acid derivatives as defined herein contain a pendant—COOH group or a pharmaceutically acceptable salt thereof e.g. in theform of a —COO⁻Na⁺ group.

[0025] The oxicams for use herein include, but are not limited to,piroxicam, sudoxicam, tenoxicam and isoxicam. Structurally relatedoxicams derivatives having similar analgesic and/or anti-inflammatoryproperties are also intended to be encompassed by this group.

[0026] Acetaminophen is 4′-hyroxyacetanilide. It is widely marketed,including by McNeil under the tradename Tylenol®.

[0027] Especially preferred are ibuprofen, S+ ibuprofen, ketoprofen,naproxen and acetaminophen.

[0028] With regard to dosage levels, the cyclooxygenase-2 inhibitor mustbe present in an analgesia-inducing amount and/or pain-alleviatingamount. Of the preferred mounts ranging from about 25 to about 200 mg.Preferably it is present in amounts ranging from about 100 to about 200mg. Rofecoxib maybe present in the claimed compositions in amountsranging from about 12.5 to about 50 mg. Preferably it is present inamounts ranging from about 25 to about 50 mg. Nimesulide may be presentin the claimed compositions in amounts ranging from about 50 to about300 mg. Preferably it is present in amounts ranging from about 100 about200 mg. Most preferably, it is present in an amount of about 200 mg.Meloxicam may be present in the claimed compositions in amounts rangingfrom about 3 to about 15 mg. Preferably, it is present in amountsranging from about 10 to about 15 mg. Most preferably, it is present inan amount of about 15 mg.

[0029] With regard to dosage levels of the cyclooxygenase-1 component ofthe claimed composition, it too must be present in an analgesia-inducingor pain-alleviating amount. Of the cyclooxygenase-1 inhibitors useful inthe practice of the present invention, including those that arementioned as being preferred, ibuprofen may be present in the claimedcompositions in amounts ranging from about 50 to about 400 mg.Preferably it is present in amounts ranging from about 200 to about 400mg. Most preferably, it is present in an amount of about 400 mg.Ketoprofen may be present in the claimed compositions in amounts rangingfrom about 6.5 to about 25 mg. Preferably it is present in amountsranging from about 12.5 to about 25 mg. Most preferably, it is presentin an amount of about 25 mg. Flurbiprofen may be present in the claimedcompositions in amounts ranging from about 12.5 to about 50 mg.Preferably it is present in amounts ranging from about 25 to about 50mg. Most preferably, it is present in an amount of about 50 mg.Fenoprofen may be present in the claimed compositions in amounts rangingfrom about 50 to about 100 mg. Preferably it is present in amountsranging from about 100 to about 200 mg. Most preferably, it is presentin an amount of about 200 mg. Etodolac may be present in the claimedcompositions in amounts ranging from about 100 to about 400 mg.Preferably it is present in amounts ranging from about 200 to about 400mg. Most preferably, it is present in an amount of about 400 mg.Naproxen sodium may be present in the claimed compositions in amountsranging from about 110 to about 440 mg. Preferably it is present inamounts ranging from about 200 to about 440 mg. Most preferably, it ispresent in an amount of about 220 mg. Oxaprozin may be present in theclaimed compositions in amounts ranging from about 100 to about 1200 mg.Preferably it is present in amounts ranging from about 300 to about 900mg. Most preferably, it is present in an amount of about 600 mg.Piroxicam may be present in the claimed compositions in amounts rangingfrom about 2.5 to about 40 mg. Preferably it is present in amountsranging from about 10 to about 40 mg. Most preferably, it is present inan amount of about 20 mg. Diclofenac may be present in the claimedcompositions in amounts ranging from about 12.5 to about 75 mg.Preferably it is present in amounts ranging from about 25 to about 75mg. Most preferably, it is present in an amount of about 50 mg.

[0030] If acetaminophen is to be used in the composition as acyclooxygenase-1 inhibitor, it may be present in the claimedcompositions in amounts ranging from about 200 to about 1000 mg.Preferably it is present in amounts ranging from about 500 to about 1000mg. Most preferably, it is present in an amount of about 1000 mg.

[0031] While the cyclooxygenase-2 inhibitor and the cyclooxygenase-1inhibitor need not be administered in a single tablet or other dosageunit, they must both be present in the patient at effective levels atthe same time. While it is within the scope of the invention toadminister the components of the claimed composition separately, as amatter of convenience, it is preferred that they be co-administered as asingle therapeutic composition. All modes of administrations arecontemplated, e.g., orally, rectally, intranasally, sublingual,topically, or by intravenous, intramuscular, intrastemal or subcutaneousinjection. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy.

[0032] The claimed composition will ordinarily be formulated with one ormore pharmaceutically acceptable ingredients in accordance with knownand established practice. Thus, the composition can be formulated as aliquid, powder, suspension or elixir. Formulations for oral use can beprovided as tablets, liquigel (Tm of R. P. Scherer) or hard capsulesherein the pharmacologically active ingredients are mixed with an inertsolid diluent such as calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredients are mixed withwater or miscible solvents such as propylene glycol; PEG's and ethanol,or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.

[0033] For topical administration in the mouth, the pharmaceuticalcompositions may take the form of buccal or sublingual tablet, drops orformulated in conventional manner.

[0034] For topical administration to the epidermis the compounds of theinvention may be formulated as creams, gels, ointments, sprays orlotions or as transdermal patches. Such compositions may, for example,be formulated with an aqueous or oily base with the addition of suitablethickening, gelling, emulsifying, stabilizing, dispersing, suspending,and/or coloring agents.

[0035] The compounds of the invention may be formulated for parenteraladministration by injection, conveniently intravenous, intramuscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage from e.g. in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

[0036] The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas. e.g. containingconventional suppository bases such as cocoa butter or other glyceride.

[0037] Aqueous suspensions can include pharmaceutically acceptableexcipients such as suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as naturally occurring phosphatide,e.g., lecithin, or condensation products of an alkylene oxide with fattyacids, e.g., polyoxyethylene stearate, or condensation products ofethylene oxide with long chain aliphatic alcohols, e.g,heptadecaethylene-oxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, e.g.,polyoxyethylene sorbitol monoleate or condensation products of ethyleneoxide with partial esters derived from fatty acids and hexitolanhydrides, e.g., polyoxyethylene sorbitan monoleate. The aqueoussuspensions can also contain one or more preservatives, e.g.,ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, saccharin or sodium or calcium cyclamate.

[0038] The following Examples demonstrate various embodiments of theclaimed invention. However, they should not be construed as limiting itsscope.

EXAMPLES Example 1

[0039] A modification of the acetic acid-induced writhing test (asdisclosed in Porreca, F., H. I. Mosberg, J. R. Omnaas, T. F. Burks andA. Cowan in Supraspinal and spinal potency of selective opioid agonistsin the mouse writhing test (Journal of Pharmacology and ExperimentalTherapeutics 240: 890-894, 1987)) was conducted. The mouse writhingmodel as described is commonly used to investigate analgesic efficacyand potential synergism with combinations of drugs.

[0040] Male Swiss mice weighing 25-30 g were obtained from AceLaboratories. They were each placed in individual rectangularobservation boxes and allowed to acclimate for at least 1 hour. Aplacebo vehicle of 1% Tween 80/water was prepared.

[0041] Groups of 8-10 mice each received the test agent or placebovehicle (in an amount of 0.25 ml/25 grams of body weight) orally viastomach tube. Those mice that received the placebo vehicle composed thecontrol group. After 20, 30, 40 or 60 minutes, each mouse was injectedparenterally with a 0.6% acetic acid solution (0.25 ml/25 g bodyweight).

[0042] After a further 5 minutes, the number of abdominal writhesdisplayed by each animal was counted over a ten minute period. Thenumber of writhes displayed by each animal in such 10 minute test periodwas then normalized to the mean number shown by the control (vehicle)group. Percent inhibition of writhing was expressed as:$\frac{( {{Mean}\quad {writhes}\quad {in}\quad {control}\quad {group}} ) - {( {{Writhes}\quad {by}\quad {individual}\quad {mouse}} ) \times 100}}{( {{Mean}\quad {writhes}\quad {in}\quad {control}\quad {group}} )}$

[0043] Results

[0044] A preliminary study was conducted at +30 minutes to establishantinociceptive dose-response curves for ibuprofen (obtained from SigmaChemical) and celecoxib (manufactured by G. D. Searle & Co. in 200 mgcapsules and marketed under the trademark Celebrex®), respectively. Theresults are presented in Table 1 below. An oral A₅₀ value of 29.07 mg/kg(17.57-40.58) (95% confidence limits) was obtained for ibuprofen. Thecorresponding value for celecoxib was >80 mg/kg. TABLE 1 Compound Dose(mg/kg) Mean % inhibition ± s.e.m. Ibuprofen 20 38.7 ± 11.2 40 59.4 ±9.58 80 74.0 ± 4.68 Celecoxib 20  7.5 ± 3.38 40 21.7 ± 4.17 80 28.3 ±8.34

[0045] To study the effects of the administration of the compounds incombination, one group of mice (n=8−10) received 29 mg/kg of ibuprofenfollowed immediately by an essentially inactive dose of celecoxib (20mg/kg). A second group of mice (n=8−10) received 29 mg of ibuprofenfollowed immediately by the placebo vehicle. At either +20, +40 or +60minutes following administration, the animals were injected i.p. with0.6% acetic acid (0.25 ml/25 g body weight) and run in the writhingtest. The data obtained are shown in Table 2. TABLE 2 Compound Time(min) Mean % inhibition ± s.e.m. Ibuprofen + vehicle 20 36.4 ± 3.2Ibuprofen + celecoxib 20 63.2 ± 8.7 Ibuprofen + vehicle 40 14.1 ± 6.2Ibuprofen + celecoxib 40 52.7 ± 9.6 Ibuprofen + vehicle 60 27.3 ± 8.2Ibuprofen + celecoxib 60 63.6 ± 9.2

[0046] It is clear from the data in Tables 1 and 2 that the presence ofeven an essentially inactive dose of celecoxib potentiated the ibuprofenthrough faster onset and duration of action.

Example 2

[0047] Tablets having the following formulations were manufactured inaccordance with general tablet manufacturing processing. Formula IIngredient mg/tablet % w/w Ibuprofen 200 38.6 Celecoxib 100 19.3Pregelantinized Starch 75 14.5 Microcrystalline Cellulose 60 11.6Lactose, hydrous 50 9.7 Croscarmellose Sodium 20 3.9 Colloidal SiliconeDioxide 5 1.0 Sodium Lauryl Sulfate 3 0.6 Stearic Acid 5 1.0

[0048] Formula II Ingredient mg/tablet % w/w Ketoprofen 12.5 4.8Celecoxib 100 38.5 Pregelantinized Starch 40 15.4 MicrocrystallineCellulose 50 19.3 Lactose, hydrous 40 15.4 Croscarmellose Sodium 10 3.9Colloidal Silicone Dioxide 2.5 1.0 Sodium Lauryl Sulfate 2 0.8 StearicAcid 2.6 1.0

[0049] Formula III Ingredient mg/tablet % w/w Ibuprofen 200 52.2Refocoxib 25 3.3 Pregelantinized Starch 60 15.6 MicrocrystallineCellulose 60 15.6 Lactose, hydrous 25 6.5 Croscarmellose Sodium 15 3.9Colloidal Silicone Dioxide 4 1.0 Sodium Lauryl Sulfate 3 0.8 StearicAcid 4 1.0

[0050] Formula IV Ingredient mg/tablet % w/w Ketoprofen 12.5 6.0Refocoxib 25 6.0 Pregelantinized Starch 30 14.4 MicrocrystallineCellulose 100 48 Lactose, hydrous 40 19.2 Croscarmellose Sodium 8 3.2Colloidal Silicone Dioxide 2 1.0 Sodium Lauryl Sulfate 1.5 0.7 StearicAcid 2 1.0

1. A composition consisting essentially of (a) at least onecyclooxygenase-2 inhibitor, and (b) at least one compound selected fromthe group consisting of NSAIDs, acetaminophen and mixtures thereof. 2.The composition of claim 1 wherein the cyclooxygenase-2 inhibitor isselected from the group consisting of celecoxib, meloxicam, nimesulideand rofecoxib and mixtures thereof, and component (b) is an NSAID. 3.The composition of claim 2 wherein the NSAID is selected from the groupconsisting of ibuprofen, ketoprofen, fenoprofen, flurbiprofen, paroxensodium, oxaprozin, piroxicam and mixtures thereof.
 4. The composition ofclaim 1 wherein the cyclooxygenase-2 inhibitor is celecoxib andcomponent (b) is ibuprofen.
 5. The composition of claim 4 whereincelecoxib is present in amounts ranging from about 25 to about 200 mgand ibuprofen is present in amounts ranging from about 50 to about 800mg.
 6. The composition of claim 4 wherein celecoxib is present inamounts ranging from about 100 to about 200 mg and ibuprofen is presentin amounts ranging from about 200 to about 400 mg.
 7. The composition ofclaim 4 wherein celecoxib is present in an amount of about 200 mg andibuprofen is present in an amount of about 400 mg.
 8. The composition ofclaim 1 wherein the cyclooxygenase-2 inhibitor is rofecoxib andcomponent (b) is ibuprofen.
 9. The composition of claim 8 whereinrofecoxib is present in amounts ranging from about 12.5 to about 50 mgand ibuprofen is present in amounts ranging from about 50 to about 800mg.
 10. The composition of claim 8 wherein rofecoxib is present inamounts ranging from about 25 to about 50 mg and ibuprofen is present inamounts ranging from about 200 to about 400 mg.
 11. The composition ofclaim 8 wherein rofecoxib is present in an amount of about 50 mg andibuprofen is present in an amount of about 400 mg.
 12. The compositionof claim 1 wherein the cyclooxygenase-2 inhibitor is meloxicam andcomponent (b) is ibuprofen.
 13. The composition of claim 12 whereinmeloxicam is present in amounts ranging from about 3 to about 15 mg andibuprofen is present in amounts ranging from about 50 to about 800 mg.14. The composition of claim 12 wherein meloxicam is present in amountsranging from about 10 to about 15 mg and ibuprofen is present in amountsranging from about 200 to about 400 mg.
 15. The composition of claim 12wherein meloxicam is present in an amount of about 15 mg and ibuprofenis present in an amount of about 400 mg.
 16. The composition of claim 1wherein the cyclooxygenase-2 inhibitor is nimesulide and component (b)is ibuprofen.
 17. The composition of claim 16 wherein nimesulide ispresent in amounts ranging from about 50 to about 300 mg and ibuprofenis present in amounts ranging from about 50 to about 800 mg.
 18. Thecomposition of claim 16 wherein nimesulide is present in amounts rangingfrom about 100 to about 200 mg and ibuprofen is present in amountsranging from about 200 to about 400 mg.
 19. The composition of claim 1wherein the cyclooxygenase-2 inhibitor is selected from the groupconsisting of celecoxib, meloxicam, nimesulide and rofecoxib andmixtures thereof, and component (b) is acetaminophen.
 20. Thecomposition of claim 19 wherein celecoxib is present in amounts rangingfrom about 25 to about 200 mg and acetaminophen is present in amountsranging from about 200 to about 1000 mg.
 21. The composition of claim 19wherein celecoxib is present in amounts ranging from about 100 to about200 mg and acetaminophen is present in amounts ranging from about 500 toabout 1000 mg.
 22. The composition of claim 19 wherein celecoxib ispresent in an amount of about 200 mg and acetaminophen is present inamounts ranging from about 500 to about 1000 mg.
 23. The composition ofclaim 19 wherein rofecoxib is present in amounts ranging from about 12.5to about 50 mg and acetaminophen is present in amounts ranging fromabout 200 to about 1000 mg.
 24. The composition of claim 19 whereinrofecoxib is present in amounts ranging from about 25 to about 50 mg andacetaminophen is present in amounts ranging from about 500 to about 1000mg.
 25. The composition of claim 19 wherein rofecoxib is present in anamount of about 50 mg and acetaminophen is present in an amount of about1000 mg.
 26. The composition of claim 19 wherein meloxicam is present inamounts ranging from about 3 to about 15 mg and acetaminophen is presentin amounts ranging from about 200 to about 1000 mg.
 27. The compositionof claim 19 wherein meloxicam is present in amounts ranging from about10 to about 15 mg and acetaminophen is present in amounts ranging fromabout 500 to about 1000 mg.
 28. The composition of claim 19 whereinmeloxicam is present in an amount of about 15 mg and acetaminophen ispresent in an amount of about 1000 mg.
 29. The composition of claim 19wherein nimesulide is present in amounts ranging from about 50 to about300 mg and acetaminophen is present in amounts ranging from about 200 toabout 1000 mg.
 30. The composition of claim 19 wherein nimesulide ispresent in amounts ranging from about 100 to about 200 mg andacetaminophen is present in amounts ranging from about 500 to about 1000mg.
 31. The composition of claim 19 wherein nimesulide is present in anamount of about 200 mg and acetaminophen is present in an amount ofabout 1000 mg.
 32. A method of alleviating pain and/or inflammationcomprising administering to a mammal a composition consistingessentially of (a) at least one cyclooxygenase-2 inhibitor and (b) atleast one compound selected from the group consisting of NSAIDs,acetaminophen and mixtures thereof.
 33. The method of claim 32 whereinthe cyclooxygenase-2 inhibitor is selected from the group consisting ofcelecoxib, meloxicam, nimesulide and rofecoxib and mixtures thereof, andcomponent (b) is an NSAID.
 34. The method of claim 33 wherein the NSAIDis selected from the group consisting of ibuprofen, ketoprofen,fenoprofen, flurbiprofen, naproxen sodium, oxaprozin, piroxicam andmixtures thereof.
 35. The method of claim 33 wherein thecyclooxygenase-2 inhibitor is celecoxib and component (b) is ibuprofen.36. The method of claim 33 wherein celecoxib is present in amountsranging from about 25 to about 200 mg and ibuprofen is present inamounts ranging from about 50 to about 800 mg.
 37. The method of claim33 wherein celecoxib is present in amounts ranging from about 100 toabout 200 mg and ibuprofen is present in amounts ranging from about 200to about 400 mg.
 38. The method of claim 35 wherein celecoxib is presentin an amount of about 200 mg and ibuprofen is present in an amount ofabout 400 mg.
 39. The method of claim 33 wherein the cyclooxygenase-2inhibitor is rofecoxib and component (b) is ibuprofen.
 40. The method ofclaim 33 wherein rofecoxib is present in amounts ranging from about 12.5to about 50 mg and ibuprofen is present in amounts ranging from about 50to about 800 mg.
 41. The method of claim 33 wherein rofecoxib is presentin amounts ranging from about 25 to about 50 mg and ibuprofen is presentin amounts ranging from about 200 to about 400 mg.
 42. The method ofclaim 33 wherein rofecoxib is present in an amount of about 50 mg andibuprofen is present in an amount of about 400 mg.
 43. The method ofclaim 33 wherein the cyclooxygenase-2 inhibitor is meloxicam andcomponent (b) is ibuprofen.
 44. The method of claim 43 wherein meloxicamis present in amounts ranging from about 3 to about 15 mg and ibuprofenis present in amounts ranging from about 50 to about 800 mg.
 45. Themethod of claim 43 wherein meloxicam is present in amounts ranging fromabout 10 to about 15 mg and ibuprofen is present in amounts ranging fromabout 200 to about 400 mg.
 46. The method of claim 43 wherein meloxicamis present in an amount of about 15 mg and ibuprofen is present in anamount of about 400 mg.
 47. The method of claim 33 wherein thecyclooxygenase-2 inhibitor is nimesulide and component (b) is ibuprofen.48. The method of claim 47 wherein nimesulide is present in amountsranging from about 50 to about 300 mg and ibuprofen is present inamounts ranging from about 50 to about 800 mg.
 49. The method of claim47 wherein nimesulide is present in amounts ranging from about 100 toabout 200 mg and ibuprofen is present in amounts ranging from about 200to about 400 mg.
 50. The method of claim 47 wherein nimesulide ispresent in an amount of about 200 mg and ibuprofen is present in anamount of about 400 mg.
 51. The method of claim 33 wherein thecyclooxygenase-2 inhibitor is selected from the group consisting ofcelecoxib, meloxicam, nimesulide and rofecoxib and mixtures thereof, andcomponent (b) is acetaminophen.
 52. The method of claim 51 whereincelecoxib is present in amounts ranging from about 25 to about 200 mgand acetaminophen is present in amounts ranging from about 200 to about1000 mg.
 53. The method of claim 51 wherein celecoxib is present inamounts ranging from about 100 to about 200 mg and acetaminophen ispresent in amounts ranging from about 500 to about 1000 mg.
 54. Themethod of claim 51 wherein celecoxib is present in an amount of about200 mg and acetaminophen is present in an amount of about 1000 mg. 55.The method of claim 51 wherein rofecoxib is present in amounts rangingfrom about 12.5 to about 50 mg and acetaminophen is present in amountsranging from about 200 to about 1000 mg.
 56. The method of claim 51wherein rofecoxib is present in amounts ranging from about 25 to about50 mg and acetaminophen is present in amounts ranging from about 500 toabout 1000 mg.
 57. The method of claim 51 wherein rofecoxib is presentin an amount of about 50 mg and acetaminophen is present in an amount ofabout 1000 mg.
 58. The method of claim 52 wherein meloxicam is presentin amounts ranging from about 3 to about 15 mg and acetaminophen ispresent in amounts ranging from about 200 to about 1000 mg.
 59. Themethod of claim 51 wherein meloxicam is present in amounts ranging fromabout 10 to about 15 mg and acetaminophen is present in amounts rangingfrom about 500 to about 1000 mg.
 60. The method of claim 51 whereinmeloxicam is present in an amount of about 15 mg and acetaminophen ispresent in an amount of about 1000 mg.
 61. The method of claim 51wherein nimesulide is present in amounts ranging from about 50 to about300 mg and acetaminophen is present in amounts ranging from about 200 toabout 1000 mg.
 62. The method of claim 51 wherein nimesulide is presentin amounts ranging from about 100 to about 200 mg and acetaminophen ispresent in amounts ranging from about 500 to about 1000 mg.
 63. Themethod of claim 51 wherein nimesulide is present in an amount about 200mg and acetaminophen is present in an amount of about 1000 mg.
 64. Amethod of potentiating an analgesic compound selected from the groupconsisting of NSAIDs, acetaminophen and mixtures thereof byadministering concurrently therewith at least one cyclooxygenase-2inhibitor.
 65. The method of claim 64 wherein the cyclooxygenase-2inhibitor is selected from the group consisting of celecoxib, meloxicam,nimesulide and rofecoxib and mixtures thereof, and component (b) is anNSAID.
 66. The method of claim 65 wherein the NSAID is selected from thegroup consisting of ibuprofen, ketoprofen, fenoprofen, flurbiprofen,naproxen sodium, oxaprozin, piroxicam and mixtures thereof.
 67. Themethod of claim 65 wherein the cyclooxygenase-2 inhibitor is celecoxiband component (b) is ibuprofen.
 68. The method of claim 65 wherein thecyclooxygenase-2 inhibitor is rofecoxib and component (b) is ibuprofen.69. The method of claim 64 wherein the cyclooxygenase-2 inhibitor iscelecoxib and component (b) is acetaminophen.
 70. The method of claim 64wherein the cyclooxygenase-2 inhibitor is rofecoxib and component (b) isacetaminophen.